Sequencing the entire genome, rather than just the exome, reveals more information about the genetic basis of autism spectrum disorder.

Autism Spectrum Disorder (ASD) is a highly heritable disease involving more
than 100 genes, but because of heterogeneity among affected individuals, a
more complete picture of the genetic causes has remained elusive. In the
past, scientists have used microarrays to identify copy number variations
associated with ASD and sequenced exomes or protein-coding regions of the
genome to reveal genes contributing to disease risk.

Now, a study published July 11th in the American Journal of Human Genetics has
shown that sequencing genomes in their entirety can reveal even more
information on ASD-related mutations than whole-exome sequencing because of
more uniform coverage. By providing more information about an individual’s
particular set of mutations, whole-genome sequencing could also help
clinicians develop personalized treatment strategies.

“The detection rate of mutations that we consider to be clinically relevant is
better than whole-exome sequencing studies, even based on our small sample
size of 32 families,” says study author Yong-hui Jiang, who treats
individuals with ASD and conducts research on the genetic basis of
neurodevelopmental disorders at Duke University School of Medicine. “This
approach is promising and may have a direct impact on patient diagnosis and
evaluation in the future.”

In the new study, Jiang and his collaborators used whole-genome sequencing to
detect de novo and rare inherited genetic variants in 32 families affected
by ASD. Using this sequencing approach in combination with bioinformatic
analyses, the researchers identified potentially significant variants in
half of the families examined—the highest proportion ever reported,
according to the study authors. Moreover, 11% of the de novo and clinically
relevant mutations identified in the study would probably not have been
captured by exome sequencing.

The genes implicated in Jiang’s study had previously been linked to ASD or
related condition, such as intellectual disability and seizures. In six of
the families, individuals with ASD had deleterious de novo mutations, such
as loss-of-function or damaging missense mutations. In addition, ten
families were affected by X-linked or autosomal inherited alterations.
Moving forward, the researchers plan to expand the study beyond 32 families
and conduct experiments to examine the function of the variants identified.

Still, it might some time before whole-genome sequencing studies of this kind
become the standard, given the exorbitant cost of whole-genome sequencing
and the challenges associated with data storage and bioinformatic analyses.
“The computational power required to analyze the whole-genome sequencing
data is significantly larger than for whole-exome data,” says Jiang. “We
used a supercomputer and a large bioinformatic team to handle this data. For
an individual investigator or lab, it’s probably not very practical if there
is a large sample size.”

Jiang himself will probably continue to use whole-exome sequencing in the
clinic, but he predicts that researchers will eventually switch to
whole-genome sequencing. “The question of whether whole-genome sequencing
will become more feasible is a financial issue,” says Jiang. “Technically, I
think that whole-genome sequencing is certainly better than whole-exome
sequencing. Our very small-scale study shows that whole-genome sequencing is
probably the way to go for the long term. But in practical terms,
whole-exome sequencing will probably dominate in clinical practice because
it’s a lot cheaper and the data analysis is much easier.”

Michael Ronemus, an expert in the genetic basis of ASD at Cold Spring Harbor
Laboratory, agrees. “There’s no doubt the field will switch over to
whole-genome sequencing for the purpose of discovery. It’s just a matter of
time,” says Ronemus, who was not involved in the new study. “But I don’t
think clinicians will switch over to whole-genome sequencing anytime in the
near future. Our expectation is that sooner or later we will find all of the
hundreds of genes that can cause autism, so there won’t be a lot of reason
to look elsewhere in the genome at a much greater cost.”